Suppression of LPS-induced matrix-metalloproteinase responses in macrophages exposed to phenytoin and its metabolite, 5-(p-hydroxyphenyl-), 5-phenylhydantoin

<p>Abstract</p> <p>Background</p> <p>Phenytoin (PHT) has been reported to induce gingival (gum) overgrowth (GO) in approximately 50% of patients taking this medication. While most studies have focused on the effects of PHT on the fibroblast in the pathophysiology underlying GO, few studies have investigated the potential regulatory role of macrophages in extracellular matrix (ECM) turnover and secretion of proinflammatory mediators. The aim of this study was to evaluate the effects of PHT and its metabolite, 5-(p-hydroxyphenyl-), 5-phenylhydantoin (HPPH) on LPS-elicited MMP, TIMP, TNF-α and IL-6 levels in macrophages.</p> <p>Methods</p> <p>Human primary monocyte-derived macrophages (<it>n </it>= 6 independent donors) were pretreated with 15-50 μg/mL PHT-Na⁺or 15-50 μg/mL HPPH for 1 hour. Cells were then challenged with 100 ng/ml purified LPS from the periodontal pathogen, <it>Aggregatibacter actinomycetemcomitans</it>. Supernatants were collected after 24 hours and levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TNF-α and IL-6 determined by multiplex analysis or enzyme-linked immunoadsorbent assay.</p> <p>Results</p> <p>A dose-dependent inhibition of MMP-1, MMP-3, MMP-9, TIMP-1 but not MMP-2 was noted in culture supernatants pretreated with PHT or HPPH prior to LPS challenge. MMP-12, TIMP-2, TIMP-3 and TIMP-2 were not detected in culture supernatants. High concentrations of PHT but not HPPH, blunted LPS-induced TNF-α production although neither significantly affected IL-6 levels.</p> <p>Conclusion</p> <p>The ability of macrophages to mediate turnover of ECM via the production of metalloproteinases is compromised not only by PHT, but its metabolite, HPPH in a dose-dependent fashion. Further, the preferential dysregulation of macrophage-derived TNF-α but not IL-6 in response to bacterial challenge may provide an inflammatory environment facilitating collagen accumulation without the counteracting production of MMPs.</p

Raccontare il mondo, descrivere la natura. L’opera di Alexander von Humboldt tra letteratura e scienza

Descritto dai suoi contemporanei come uno degli uomini più celebri della sua epoca, Alexander von Humboldt (1769-1859) è stato uno dei personaggi più ammirati del XIX secolo. Fratello minore di Wilhelm, Alexander fu insieme e nello stesso tempo botanico, naturalista, esploratore e geografo. Nel 1799 si imbarcò insieme ad Aimé Jacques Alexandre Bonpland (1773-1858) in un viaggio che li condusse prima a Tenerife, quindi in Venezuela, Colombia, Cuba, Ecuador, Perù e Messico. Frutto di questo e di altri avventurosi viaggi è una nutrita produzione letteraria e scientifica che in questo volume viene indagata unitamente alle numerose sfaccettature della figura di Humboldt e ai molteplici influssi della sua opera e del suo pensiero in ambito storico, geografico, letterario e linguistico

Enhancing structure relaxations for first-principles codes: an approximate Hessian approach

We present a method for improving the speed of geometry relaxation by using a harmonic approximation for the interaction potential between nearest neighbor atoms to construct an initial Hessian estimate. The model is quite robust, and yields approximately a 30% or better reduction in the number of calculations compared to an optimized diagonal initialization. Convergence with this initializer approaches the speed of a converged BFGS Hessian, therefore it is close to the best that can be achieved. Hessian preconditioning is discussed, and it is found that a compromise between an average condition number and a narrow distribution in eigenvalues produces the best optimization.Comment: 9 pages, 3 figures, added references, expanded optimization sectio

Residual strength of WC-Co cemented carbides after being subjected to abrupt temperature changes

Thermal shock and thermal fatigue are recognized as common failure modes for WC - Co cemented carbides (hardmetals) in several applications in volving service temperature changes. However, information on microstructure - performance for these materials when subjected to abrupt changes in temper ature is rather limited. In this investigation, the thermal shock resistance of two WC - Co cemented carbides is studied on the basis of their residual strength after being subjected to temperature changes. The materials studied correspond to grades with dif ferent grain size (medium and ultrafine) but similar binder content. Thermal shock variables include two temperature difference ranges (400ºC and 550ºC) as well as number of abrupt changes (1, 3 and 10). Residual strength results were related to parameters extracted from Hasselman’s theory . It is found that medium - sized hardmetal exhibits a higher strength loss in the first quenching cycle but a greater damage tolerance to repeated thermal shocks than the ultrafine - sized. The assessed residual strength tren ds are in agreement with those expected from evaluation of Hasselman’s parameters for quantifying resistance to either crack initiation or crack propagation induced by thermal shockPostprint (published version